The present invention relates to intermediates useful for the manufacture of carbapenem compound useful as antibacterial agents and also to a method for manufacturing the same.
With regard to antibiotics of a carbapenem series, synthetic studies for many compounds have been carried out since the discovery of thienamycin in 1976. Recently, there are many studies on carbapenem compounds having a 2-substituted pyrrolidine-4-thio group at the 2-position of a carbapenem skeleton and, among them, there is a disclosure on the following carbapenem compounds having an excellent antibacterial activity to Pseudomonas aeruginosa in Drugs of the Future, 1996, 21(4):361-365. 
In addition, compounds related thereto are disclosed in JP-A 8-73462 etc.
Manufacture of the carbapenem compounds described in those reports are carried out by a condensation of a reactive compound of a carbapenem skeleton with an optically active pyrrolidine-4-thiol compound (VIII): 
(wherein, PNZ is a p-nitrobenzyloxycarbonyl group), and the optically active pyrrolidine-4-thiol compound (VIII) is manufactured according to the steps as shown in the following reaction formulae: 
(wherein, Boc is a tert-butoxycarbonyl group, PNZ is a p-nitrobenzyloxycarbonyl group and TBDMS is a tert-butyldimethylsilyl group.)
However, according to the disclosed method, a diastereomer having the unnecessary configuration is also obtained in the first step and, therefore, there is the following industrial disadvantage judging from preparing the diastereomer having the desired configuration only. Thus, 1) the diastereomer having the unnecessary configuration is to be separated and removed; and 2) yield of the diastereomer having the desired configuration is low.
An object of the present invention is to overcome the above disadvantages or, in other words, to manufacture only the diastereomer having the desired configuration selectively and in a high yield.
As a result of an intensive investigation, the present inventors have found that the method for the manufacture of stereoselective pyrrolidine-4-thiol compounds as mentioned below is able to solve the above problems and have accomplished the present invention.
Namely, the present invention is a method for the manufacture of (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidine-4-thiol represented by the formula (II): 
(wherein, n is an integer of 1 to 4) or a salt thereof, which comprises the steps of treating a (2S,4R)-pyrrolidine-2-carbaldehyde compound represented by the formula (III): 
(wherein, R1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; and R2 is a protecting group for an amino group) with a (4R)-3-(xcfx89-substituted alkanoyl)oxazolidin-2-one (or thiazolidin-2-thione) compound represented by the formula (IV): 
(wherein, R3is a substituted or unsubstituted lower alkyl group or an aryl group; X is an oxygen atom or a sulfur atom; Y is an azide group or a nitro group; and m is an integer of 2 to 5) to give a (4R)-[3-[2-(xcfx89-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S,4R)-2-pyrrolidinyl]propyl]oxazolidin-2-one (or thiazolidin-2-thione) compound represented by the formula (I): 
(wherein, R1 is a lower alkylsufonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R2 is a protecting group for an amino group; R3 is a substituted or unsubstituted lower alkyl group or an aryl group; X is an oxygen atom or a sulfur atom; Y is an azide group or a nitro group; and n is an integer of 1 to 4); reducing the azide group or the nitro group thereof to give a (3S)-[[(R)-hydroxy-(2S,4R)-2-pyrrolidinyl]methyl]lactam compound represented by the formula (V): 
(wherein, R1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R2 is a protecting group for an amino group; and n is an integer of 1 to 4); reducing the carbonyl group therein with or without protecting the NH group of the resulting cyclic amide to give a (2S,4R)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidine compound represented by the formula (VI): 
(wherein, R1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R2 is an protecting group for an amino group; R4 is a hydrogen atom or a protecting group for an amino group; and n is an integer of 1 to 4); when R1 is an alkylsilyl group, eliminating the alkylsilyl group selectively, followed by converting to a lower alkylsulfonyl group or an optionally substituted arylsulfonyl group and making it into an acylthio group to give a (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]-4-acylthiopyrrolidine compound represented by the formula (VII): 
(wherein, R2 is a protecting group for an amino group; R4 is a hydrogen atom or a protecting group for an amino group; R5 is an acyl group; and n is an integer of 1 to 4); and then eliminating the protecting group(s). Further, the present invention relates to novel intermediates, i.e. a (4R)-[3-[2-(xcfx89-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S,4R)-2-pyrrolidinyl]propyl]oxazolidin-2-one (or thiazolidine-2-thione) compound and (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidin-4-thiol or salts thereof.
A (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidin-4-thiol, which is a novel intermediate, is capable of forming a salt in the presence of an acid and it goes without saying that such a salt is also covered by the present invention. Examples of the salt include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, trifluoroacetate and sulfonates such as methanesulfonate, p-toluenesulfonate, etc.
In the present invention, examples of the lower alkylsulfonyl group found in the definition for R1 include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, etc.; examples of the arylsulfonyl group found therein include a phenylsulfonyl group, a p-toluenesulfonyl group, etc.; and examples of the alkylsilyl group found in the definition for R1 include a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, an tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a vinyldimethylsilyl group, etc.
Examples of the protecting group for an amino group found in the definitions of R2 and R4 include substituted or unsubstituted lower alkanoyl groups such as a formyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a propionyl group, a phenylacetyl group, a thienylacetyl group, etc., or substituted or unsubstituted lower alkoxycarbonyl groups such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-bromobenzyloxycarbonyl group, a 2,4-dichlorobenzyloxycarbonyl group, etc.
Examples of the substituted or unsubstituted lower alkyl group found in the definition of R3 include a methyl group, an ethyl group, an isopropyl group, a benzyl group, etc., while an example of the aryl group found therein include a phenyl group, etc.
Examples of the acyl group found in the definition of R5 include the groups derived from saturated or unsaturated fatty acids such as a formyl group, an acetyl group, a propionyl group, an acryloyl group, etc., the groups derived from carbocyclic carboxylic acids such as a cyclohexylcarbonyl group, a benzoyl group, a toluoyl group, a cinnamoyl group etc., the groups derived from heterocyclic carboxylic acids such as a nicotinoyl group, a thenoyl group etc., a morpholinylacetyl group, a thiomorpholinylacetyl group, etc.
The manufacturing method according to the present invention will be described in more detail as follows. 
(wherein, R1 is a lower alkylsulfonyl group, an optionally substituted arylsulfonyl group or an alkylsilyl group; R2 is a protecting group for an amino group; R3 is a substituted or unsubstituted lower alkyl group or an aryl group; R4 is a hydrogen atom or a protecting group for an amino group; R5 is an acyl group; X is an oxygen atom or a sulfur atom; Y is an azide group or a nitro group; m is an integer of 2 to 5; and n is an integer of 1 to 4.)
(Step A)
This step is that where a (4R)-[3-[2-(xcfx89-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S,4R)-2-pyrrolidinyl]propyl]oxazolidin-2-one (or thiazolidine-2-thione) compound having a desired configuration is selectively manufactured by means of an asymmetric aldol reaction by the reaction of a (2S,4R)-pyrrolidine-2-carbaldehyde compound with (4R)-3-(xcfx89-substituted alkanoyl)oxazolidin-2-one (or thiazolidine-2-thione) compound in an aprotic solvent in the presence of a base. Examples of the base include n-butyl lithium (n-BuLi), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) etc. and, among them, lithium bis(trimethylsilyl)amide, (LHMDS) is particularly preferred. Examples of the aprotic solvent include diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyl-2-imidazolidinone (DMI), dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), etc. The reaction is carried out at from xe2x88x9240xc2x0 C. to xe2x88x92100xc2x0 C.
(Step B)
This step is that where an azide group or a nitro group of a (4R)-[3-[2-(xcfx89-substituted alkyl)-3-(R)-hydroxy-1-oxo-3-(2S,4R)-2-pyrrolidinyl]propyl]oxazolidin-2-one (or thiazolidine-2-thione) compound is reduced and, at the same time, an oxazolidinyl group or a thiazolidinyl group is eliminated whereupon a lactam ring is formed. The reduction is carried out by means of a catalytic reduction using palladium-carbon, platinum oxide catalyst, etc. or using sodium borohydride. Although there is no particular limitation for the solvent in the catalytic reduction, the use of tetrahydrofuran (THF) is preferred. When sodium borohydride is used, the use of an alcoholic solvent, particularly isopropyl alcohol, is preferred.
An optically active oxazolidin-2-one compound or thiazolidine-2-thione compound which is produced in this reaction is recovered and is recycled in the manufacture the of (4R)-3-(xcfx89-substituted alkanoyl)oxazolidin-2-one (or thiazolidine-2-thione) compound.
(Step C)
This step is that where a carbonyl group of the lactam compound produced in the step B is reduced to give a cyclic amine compound. The reduction is carried out with or without protecting the NH group of the lactam ring. Examples of the reducing agent used here include aluminum reducing agents such as aluminum hydride, lithium aluminum hydride, lithium trimethoxyaluminohydride, etc.; diborane; and borane complexes such as a dimethyl sulfide-borane complex, a trimethylamine-borane complex in the presence of a Lewis acid and, among them, a dimethyl sulfide-borane complex is preferred. Examples of the reaction solvent include those which do not participate in the reaction such as tetrahydrofuran (THF), dioxane, diglyme (DGM), etc. Protection of the NH group in the lactam ring is carried out by an acid chloride such as acetyl chloride, benzoyl chloride, etc., an acid anhydride such as acetic anhydride, etc., a substituted lower alkyloxycarbonyl halogenide such as p-nitrobenzyloxycarbonyl chloride, etc., or di-tert-butyl dicarbonate, etc. in the presence of a base such as dimethylaminopyridine, etc. in a solvent such as acetone, acetonitrile, tetrahydrofuran (THF), dioxane, etc.
(Step D)
This step is that where a lower alkylsulfonyloxy group or an optionally substituted arylsulfonyl group at the 4-position in an R-configuration in a pyrrolidine ring of (2S,4R)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]pyrrolidine compound (when R1 is an alkylsilyl group, the alkylsilyl group is selectively eliminated and converted to a lower alkylsulfonyl group or an optionally substituted arylsulfonyl group) is converted to an acylthio group in an S-configuration. The reaction is carried out either with a thiocarboxylate such as potassium thioacetate or sodium thioacetate in a polar solvent such as acetonitrile, acetone, 1,2-dimethyl-2-imidazolidinone (DMI), dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), etc., or with a thiocarboxylic acid such as thioacetic acid, thiobenzoic acid, etc., in the presence of a base such as potassium carbonate, cesium carbonate, etc.
(Step E)
This step is that where an acyl group in an acylthio group of a (2S,4S)-2-[[(R)-hydroxy-(3R)-cyclic amine-3-yl]methyl]-4-acylthiopyrrolidine compound and a protecting group for an amino group on a pyrrolidine ring is, and, if an amino group on another cyclic amine ring has a protecting group, this protecting group is also, eliminated. The reaction is carried out in an alcoholic solvent such as methanol, ethanol etc., or tetrahydrofuran (THF) or dioxane in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, etc. The reaction may also be carried out by treating with an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide in the above-mentioned solvent. Further, when a protecting group for the amino group is a reductively eliminated group such as a benzyloxycarbonyl group, a nitrobenzyloxycarbonyl group etc., it is also possible that the protecting group is firstly eliminated by means of reduction and then the acyl group in the acylthio group is eliminated by the above-mentioned acid or alkali.